Abstract: Viruses of the arthropod-borne Flavivirus genus infect over 200 million people worldwide each year, resulting in a significant disease burden in regions where such pathogens are endemic. Although vaccines exist for some of these viruses, there is currently neither effective vaccine nor specific therapy for West Nile virus (WNV) or Zika virus (ZIKV). During infection of the host cell, a single viral polyprotein is synthesized from the viral genome. This polyprotein is cleaved into its component proteins by a combination of host cell proteases and a two-component viral protease, encoded in genes NS2B and NS3. The function of this viral protease is essential for virus assembly and replication. We previously identified several existing drugs, including Temoporfin and erythrosin B, that are potent and broad-spectrum flavivirus inhibitors. The major goal of this proposal is to perform in vivo pharmacokinetics and efficacy studies to establish whether these two drugs, Temoporfin and Erythrosin B, are effective in animal models of ZIKV and DENV2. These studies are essential for drug repurposing. The approval of new compounds as drugs by governmental drug administration agencies requires significant effort, time, and expense. If drugs that are already approved for treatment have additional capabilities that can be exploited therapeutically, repurposing them is the fastest route to develop new therapies.